ABSTRACT Gestational diabetes mellitus (GDM) heightens the risk of developing cardiovascular disease in both mother and offspring. A recent large population-based prospective study (CARDIA) found that GDM is independently associated with cardiac hypertrophy and impaired heart function later in life. In agreement with this finding, our preliminary data show cardiac hypertrophy and activation of Ca2+-dependent transcriptional signaling two months after a GDM-complicated pregnancy in female rats. Although hyperglycemia is generally considered the critical mediator, numerous studies reported that GDM has negative long term consequences even with good glycemic control in the mother. Thus, additional mechanisms promote metabolic and cardiovascular dysfunction in GDM. We previously demonstrated an essential role for amylin, a pancreatic hormone with amyloidogenic properties and whose secretion increases in parallel with that of insulin, in the cardiac remodeling and dysfunction induced by type-2 diabetes. Moreover, we found that amylin activates Ca2+- dependent transcriptional signaling in cardiac myocytes. Our preliminary studies show higher amylin levels in blood from female rats with GDM and their offspring. Based on these findings, we hypothesize that GDM promotes pathological remodeling of maternal and offspring heart through activation of Ca2+-dependent hypertrophy signaling that is triggered by systemic amylin dyshomeostasis. To test this overall hypothesis, we will i) determine the molecular mechanisms underlying the GDM-induced pathological remodeling of the heart, ii) probe the amylin-cardiac myocyte interaction in GDM, and iii) assess the effect of hyperamylinemia on pregnancy-induced cardiac remodeling in the absence of other metabolic alterations associated with GDM. Experiments will combine in vivo assessment of heart structure and function and pharmacological treatment with measurements in explanted hearts and isolated cardiac myocytes in female rats with normal and GDM- complicated pregnancies and their offspring as well as in pregnant amylin-KO females injected with recombinant amylin. Thus, the project will provide unique insights into the complex mechanisms through which GDM programs cardiac remodeling in mother and offspring. The study may be paradigm shifting by asserting amylin dyshomeostasis as a key player in this pathology, which will help design new therapeutic strategies for reducing the postpartum risk of heart disease in mothers with GDM and their offspring.